Doxorubicin (DOX) hydrochloride and epirubicin are commercially available anti-tumor antibiotics with a broad anti-tumor spectrum, killing many kinds of tumor cells, and the mechanism underlying is mainly the inhibition on the synthesis of nucleic acids upon the doxorubicin molecule inserting into DNA. Doxorubicin hydrochloride and epirubicin can be used to treat hematological tumors and solid tumors, such as breast cancer, ovarian cancer, sarcoma, and many other solid tumors. However, the dose of this kind of anthracycline compounds is restricted in clinical use because they bring serious toxicity or side effect. Doxorubicin hydrochloride can cause various unwanted effects, including bone marrow toxicity, gastrointestinal diseases, stomatitis, alopecia, exosmosis, acute and cumulative cardiac toxicity. A main limitation of doxorubicin hydrochloride lies in that, after each course of treatment, a great dose of doxorubicin hydrochloride leads to sharp reduction of monocytes and platelets in bone marrow and blood. A major concern is that a cumulative cardiac toxicity may induce a myocardial congestive heart failure, which is irreversible.
Doxorubicin (DOX) and epirubicin were functionally modified to produce effective doxorubicin based anti-tumor drugs having lower side effect.
Inventors of the subject application reported the structures and biological effects of Legubicin (BOC-AANL-DOX (SEQ ID NO: 2)) and LEG3 (Succinyl-AANL-DOX (SEQ ID NO: 2)) in Cancer Research in 2003 and 2006. However, further investigation on the drugs showed that each of both compounds is only provided with a single-targeting ability. And they had a short metabolic half-life, which leads to insufficient concentration and duration necessary for drug activation at the tumor site, and in turn, low efficacy in an animal model. Thus, they are not ideal anti-tumor drugs.
Therefore, targeting doxorubicin- and/or epirubicin-based drugs with reduced toxicity of doxorubicin hydrochloride and epirubicin and high efficacy as anti-tumor agents are in special need.